Possible Role of the Antibiotic-Modified Microbiome in the Development of Hematological Malignancies in European Countries

Hematological malignancies are considered the fifth most common cancer in the world. Several risk factors and probable etiological agents have been suspected in the pathomechanism of those malignancies as infections, chemicals, irradiation, etc., and recently, the contribution of the altered gut flora, dysbiosis, was identified also as a possible additional factor to the existing ones. Host, and external factors, like antibiotics, which were identified as a major disruptor of the "normal" gut flora, influence the composition of the microbiome. Considering the several-fold differences in antibiotic consumption patterns and the incidence of hematological malignancies in European countries, the hypothesis was raised that the dominant consumption of certain antibiotic classes might influence the incidence of different hematological malignancies through the modification of gut flora. Comparisons were performed between the average antibiotic consumption databases reported yearly by ECDC (2009-2019) and the incidence rate of Hodkin lymphoma (HL), non-Hodgkin lymphoma (NHL), multiple myeloma (MM), and leukemia (LEU) estimated for 2020 in 30 European countries. Applying Spearman calculations, significant positive correlation has been found between the incidence of HL and tetracycline (J01A) consumption (r = 0.399, p = 0,029), NHL and narrow spectrum, beta-lactamase resistant penicillin (J01CF) (r = 0.580, p = 0,001), MM and tetracycline (r = 0.492, p = 0.006), penicillin (J01C) (r = 0.366, p = 0.047), narrow spectrum, beta-lactamase resistant penicillin (J01CF) (r = 0.574, p = 0.001), while strong, significant negative correlation has been recorded between NHL and cephalosporin (r = -0,460, p = 0,011), and quinolone (r = -0,380, p = 0,038). The incidence of LEU did not show any positive or negative association with any antibiotic classes. It is concluded that certain antibiotic classes, in addition to other putative factors, might promote or inhibit the development of different hematological malignancies.

Microbiome Compositions and Resistome Levels after Antibiotic Treatment of Critically Ill Patients: An Observational Cohort Study

Hospitalization and treatment with antibiotics increase the risk of acquiring multidrug-resistant bacteria due to antibiotic-mediated changes in patient microbiota. This study aimed to investigate how broad- and narrow-spectrum antibiotics affect the gut microbiome and the resistome in antibiotic naïve patients during neurointensive care. Patients admitted to the neurointensive care unit were treated with broad-spectrum (meropenem or piperacillin/tazobactam) or narrow-spectrum antibiotic treatment (including ciprofloxacin, cefuroxime, vancomycin and dicloxacillin) according to clinical indications. A rectal swab was collected from each patient before and after 5–7 days of antibiotic therapy (N = 34), respectively. Shotgun metagenomic sequencing was performed and the composition of metagenomic species (MGS) was determined. The resistome was characterized with CARD RGI software and the CARD database. As a measure for selection pressure in the patient, we used the sum of the number of days with each antibiotic (antibiotic days). We observed a significant increase in richness and a tendency for an increase in the Shannon index after narrow-spectrum treatment. For broad-spectrum treatment the effect was more diverse, with some patients increasing and some decreasing in richness and Shannon index. This was studied further by comparison of patients who had gained or lost >10 MGS, respectively. Selection pressure was significantly higher in patients with decreased richness and a decreased Shannon index who received the broad treatment. A decrease in MGS richness was significantly correlated to the number of drugs administered and the selection pressure in the patient. Bray–Curtis dissimilarities were significant between the pre- and post-treatment of samples in the narrow group, indicating that the longer the narrow-spectrum treatment, the higher the differences between the pre- and the post-treatment microbial composition. We did not find significant differences between pre- and post-treatment for both antibiotic spectrum treatments; however, we observed that most of the antibiotic class resistance genes were higher in abundance in post-treatment after broad-spectrum treatment.

Antibiotic Consumption Patterns in European Countries Might Be Associated with the Prevalence of Diabetes Type-1-2 (T1D, T2D)

Several publications have raised the issue that the development of diabetes is preceded by alteration of the microbiome (dysbiosis) and hence, the role of environmental factors, triggering dysbiosis, should be considered. Antibiotics are powerful agents inducing dysbiosis and the authors wanted to explore the possible relationship between the consumption of different major classes of antibiotics and the prevalence of diabetes (type-1, /T1D/, type-2 /T2D/) in thirty European countries. According to our hypothesis, if such association exists, the dominant use of certain major antibiotic classes might be reflected in the prevalence of T1D and T2D in different countries. Comparisons were performed between the prevalence of diabetes (T1D and T2D) estimated for 2019 and featured in the Diabetes Atlas with the average yearly consumption of major antibiotic classes of the previous 10 years (2010-19) extracted from the ECDC yearly reports on antibiotic consumption in Europe. Pearson correlation and variance analysis were used to estimate the possible relationship. Strong, positive (enhancer) associations were found between the prevalence of T1D and the consumption of tetracycline (J01A /p: 0.001/) and the narrow spectrum penicillin (J01CE /p: 0,006/, CF /p: 0.018/). Strong negative (inhibitor) association was observed with broad-spectrum, beta-lactamase resistant penicillin (J01CR /p: 0.003/), macrolide (J01F /p: 0.008/) and quinolone (J01M /p: 0.001/). T2D showed significant positive associations with cephalosporin (J01D /p: 0.048/) and quinolone (J01M /p: 0.025/), and a non-significant negative association was detected with broad-spectrum, beta-lactamase-sensitive penicillin (J01CA /p: 0.67/). Countries with the highest prevalence of diabetes (first 10 positions) showed concordance with the higher consumption of “enhancer” and the lower consumption of “inhibitor” antibiotics (first 10 positions) as indicated by variance analysis. Countries with high prevalence of T1D showed high consumption of tetracycline (p: 0.015), and narrow spectrum, beta-lactamase sensitive penicillin (p: 0.008), and low consumption of “inhibitor” antibiotics (broad-spectrum, beta-lactamase resistant, combination penicillin (p: 0.005), cephalosporin (p: 0.036), and quinolone (p: 0.003). Countries with a high prevalence of T2D consumed more cephalosporin (p: 0.084), quinolone (p: 0.54), and less broad-spectrum, beta-lactamase sensitive penicillin (p: 0.012) than other countries. Conclusion/Interpretation: The development of diabetes-related dysbiosis might be attached to higher consumption of specific classes of antibiotics, showing positive (enhancer) associations with the prevalence of diabetes, and the low consumption of other classes of antibiotics shoving negative (inhibitory) associations. Those groups of antibiotics are different in T1D and T2D

Impact analysis of expanding narrow-spectrum antibiotic use for children with ear, sinus and throat infections

Aim: Estimate the impacts treating acute respiratory tract infections (ARTIs) in children aged 6 months through 12 years with narrow-spectrum antibiotics. Materials & methods: Decision-tree model to estimate children’s health, healthcare utilization and costs, and caregiver’s time and costs for using narrow-spectrum antibiotics in eligible children with an ARTI, compared with current use of narrow- and broad-spectrum antibiotics. Results: Reduced adverse drug reactions by 35,750 (14%) cases) and 4750 (12%) fewer emergency department visits, 300 (12%) fewer hospitalizations, and 50,500 (10%) avoided outpatient visits. Annual healthcare costs fell by US$120 million (22%). Total societal costs declined by US$131 million (20%). Conclusion: National implementation of narrow-spectrum antibiotics to treat ARTIs in children improves patient outcomes and reduces caregiver burden and annual healthcare costs.

Antipseudomonal vs narrow-spectrum agents for the treatment of community-onset intra-abdominal infections

Background Antipseudomonal antibiotics are often used to treat community-acquired intra-abdominal infections (CA-IAI) despite common causative pathogens being susceptible to more narrow-spectrum agents. The purpose of this study was to compare treatment-associated complications in adult patients treated for CA-IAI with antipseudomonal versus narrow-spectrum regimens. Methods This retrospective cohort study included patients >18 years admitted for CA-IAI treated with antibiotics. The primary objective of this study was to compare 90-day treatment-associated complications between patients treated empirically with antipseudomonal versus narrow-spectrum regimens. Secondary objectives were to compare infection and treatment characteristics along with patient outcomes. Sub-group analyses were planned to compare outcomes of patients with low-risk and high-risk CA-IAI and patients requiring surgical intervention versus medically managed. Results A total of 350 patients were included: Antipseudomonal, n=204; Narrow-spectrum, n=146. There were no differences in 90-day treatment-associated complications between groups (Antipseudomonal 15.1% vs Narrow-spectrum 11.3%, p=0.296). Additionally, no differences were observed in hospital LOS, 90-day readmission, C. difficile, or mortality. In multivariate logistic regression, treatment with a narrow-spectrum regimen (OR 0.75 [95% C.I 0.39-1.45] was not independently associated with the primary outcome. No differences were observed in 90-day treatment-associated complications for patients with low-risk (Antipseudomonal 15% vs Narrow-spectrum 9.6%, p=0.154) or high-risk CA-IAI (Antipseudomonal 15.8% vs Narrow-spectrum 22.2%, p=0.588), or those who were surgically (Antipseudomonal 8.5% vs Narrow-spectrum 9.2%, p=0.877) or medically managed (Antipseudomonal 23.1 vs Narrow-spectrum 14.5, p=0.178). Conclusion Treatment-associated complications were similar among patients treated with antipseudomonal and narrow-spectrum antibiotics. Antipseudomonal therapy is likely unnecessary for most patients with CA-IAI.

Staphylococcus aureus - selective reporting of antibiogram results and its impact on antibiotic use: Interventional study with a reference group on the effect of switching from non-selective to selective antibiotic reporting

Background Antimicrobial stewardship (AMS) strategies worldwide focus on optimising the use of antibiotics. Selective susceptibility reporting is recommended as an effective AMS tool although there is a lack of representative studies investigating the impact of selective susceptibility reporting on antibiotic use. The aim of this study was to investigate the impact of selective susceptibility reporting of Staphylococcus aureus (S. aureus) on antibiotic consumption. Enhancing the use of narrow-spectrum beta-lactam antibiotics such as flucloxacillin/cefazolin/cefalexin is one of the main goals in optimising antibiotic therapy of S. aureus infections. Methods This interventional study with control group was conducted at a tertiary care hospital in Germany. During the one-year interventional period susceptibility reports for all methicillin-sensitive S. aureus (MSSA) were restricted to flucloxacillin/cefazolin/cefalexin, trimethoprim-sulfamethoxazole, clindamycin, gentamicin and rifampin/fosfomycin, instead of reporting all tested antibiotics. The impact of implementing selective reporting was analysed by monitoring total monthly antibiotic consumption in our hospital and in a reference hospital (recommended daily dose/100 occupied bed days: RDD/100 BD), as well as on an individual patient level by analysing days of therapy adjusted for bed days (DOT/ 100 BD) for patients with S. aureus bacteremia (SAB) and respectively skin and soft tissue infections (SSTI). Results MSSA-antibiograms were acquired for 2836 patients. The total use of narrow-spectrum beta-lactams more than doubled after implementing selective reporting (from 1.2 to 2.8 RDD/100 BD, P < 0.001). The use of intravenous flucloxacillin/cefazolin for SAB rose significantly from 52 to 75 DOT/100 BD (plus 42%), just as the use of oral cefalexin for SSTI (from 1.4 to 9.4 DOT/100 BD, from 3 to 17 of 85/88 patients). Considering the overall consumption, there was no decrease in antibiotics omitted from the antibiogram. This was probably due to their wide use for other infections. Conclusions As narrow-spectrum beta-lactams are not widely used for other infections, their increase in the overall consumption of the entire hospital was a strong indicator that selective reporting guided clinicians to an optimised antibiotic therapy of S. aureus infections. On a patient level, this assumption was verified by a significant improved treatment of S. aureus infections in the subgroups of SAB and SSTI. As useful AMS tool, we recommend implementing selective reporting rules into the national/international standards for susceptibility reporting.

1216. Presence of the Narrow-Spectrum OXA-1 Beta-lactamase Enzyme Is Associated with Elevated Piperacillin-Tazobactam MIC Values Among ESBL-producing Escherichia coli Clinical Isolates (CANWARD, 2007-2018)

Background The clinical outcome of patients with bacteremia due to an extended-spectrum beta-lactamase (ESBL)-producing member of the family Enterobacteriaceae who are treated with piperacillin-tazobactam appears to depend, at least in part, on the piperacillin-tazobactam MIC. The purpose of this study was to determine whether there is any association between the MIC of piperacillin-tazobactam and presence of the narrow spectrum OXA-1 beta-lactamase enzyme among ESBL-producing Escherichia coli. Methods E. coli clinical isolates were obtained from patients evaluated at hospitals across Canada (January 2007 to December 2018) as part of an ongoing national surveillance study (CANWARD). ESBL production was confirmed using the Clinical and Laboratory Standards Institute phenotypic method. Susceptibility testing was carried out using custom broth microdilution panels, and all isolates underwent whole genome sequencing for beta-lactamase gene detection. Results In total, 671 ESBL-producing E. coli were identified as part of the CANWARD study. The majority of isolates (92.0%; 617/671) harbored a CTX-M ESBL enzyme. CTX-M-15 (62.3%; 418/671), CTX-M-27 (13.9%; 93/671), and CTX-M-14 (13.4%; 90/671) were the most common variants identified. The narrow spectrum OXA-1 beta-lactamase enzyme was present in 42.6% (286/671) of isolates. OXA-1 was detected in 66.3% (277/418) of isolates with a CTX-M-15 ESBL enzyme versus only 3.6% (9/253) of isolates with other ESBL enzyme types. The piperacillin-tazobactam MIC50 and MIC90 values were 8 µg/mL and 32 µg/mL for isolates that possessed the OXA-1 enzyme versus 2 μg/mL and 8 µg/mL for those that did not. The percentage of ESBL-producing E. coli isolates that were inhibited by a piperacillin-tazobactam MIC of ≤8 μg/mL was 68.5% for isolates that were OXA-1 positive and 93.8% for isolates that were OXA-1 negative. Conclusion The MIC50 and MIC90 values of piperacillin-tazobactam among ESBL-producing E. coli were higher for the subset of isolates that harbored a narrow spectrum OXA-1 beta-lactamase enzyme relative to the subset that did not. This association was primarily observed among ESBL-producers with the CTX-M-15 enzyme variant. OXA-1 was infrequently detected among isolates with other ESBL enzyme types. Disclosures George Zhanel, PhD, AVIR (Grant/Research Support)Iterum (Grant/Research Support)Merck (Grant/Research Support)Pfizer (Grant/Research Support)Sandoz (Grant/Research Support)Sunovion (Grant/Research Support)Venatorx (Grant/Research Support)Verity (Grant/Research Support)

61. A Multidisciplinary Quality Improvement Initiative to Promote Penicillin Allergy Delabeling

Background Penicillin (PCN) allergies are reported in up to 10% patients and are associated with adverse clinical and antimicrobial stewardship outcomes. Here we describe a multidisciplinary quality improvement (QI) initiative to facilitate PCN delabeling at a large urban hospital. Methods Starting in August 2020, the departments of Allergy and Infectious Diseases (ID) began a joint QI effort to employ a part time allergist nurse practitioner (ANP) for PCN allergy assessment and delabeling. The ANP used a daily system generated list to identify and assess adult patients with PCN allergy and contact teams to request a consult. An ID fellow also assisted with identifying patients and contacting care teams. The ANP then offered skin/oral PCN challenge or direct label removal based on history after discussion with an allergist physician. Baseline, clinical, and allergy characteristics were compared between patients delabeled and not delabeled using Chi-square and Mann-Whitney U test. Primary endpoints were antibiotic utilization outcomes from index admission post ANP assessment to 30-days post discharge. Secondary endpoints included readmission, length of stay (LOS), mortality, and sustained removal of the PCN allergy at 30-days. Results Between 30 August 2020 and 6 May 2021 (250 days), 139 PCN allergic patients were assessed (81 delabeled versus 58 not delabeled) (Figure 2). Some patients (37%) were delabeled via history alone, while 63% had further skin/oral testing. Baseline characteristics were similar between groups (Table 1). In the delabeled group, we observed increased narrow-spectrum PCN use (p&lt; 0.001), and decreased vancomycin (p&lt; 0.001), fluoroquinolone (p=0.013), carbapenem (p&lt; 0.011), and overall restricted antimicrobial use (Table 2). Rates of 30-day readmission, LOS, and mortality were comparable. Four (5%) of delabeled patients had had PCN allergy re-entered in the chart at 30-days. Patients were similar between groups on all baseline clinical and allergy characteristics except for more patients with infection classified as “other” in the non-delabeled group. In the delabeled patients, we observed increased narrow-spectrum PCN use and decreased vancomycin, fluoroquinolone, carbapenem, and overall restricted antimicrobial use. Use of first and second generation cephalosporines was comparable between groups. Rates of 30-day readmission, LOS, and mortality were comparable. Conclusion This QI effort between the departments of Allergy and ID to employ an ANP increased narrow spectrum antibiotic use and reduced use of restricted antimicrobials. Challenges included the part time position of the ANP unable to see every patient, reemergence of allergy in the chart, and clinical or other exclusions for delabeling (Fig 3). Disclosures All Authors: No reported disclosures

140. Variations in Rates of Antimicrobial Use in Primary Care, in Relation to the Presence of Chronic Diseases, Québec, Canada, 2014-2017

Background Chronic diseases may increase one’s risk of infection and ensuing complications, which in turn may lower clinicians’ tolerance threshold for antimicrobial prescription, while potential drug interactions may limit therapeutic options. Objective of the study was to measure the impact of chronic diseases on the rates of antimicrobial use in the Province of Québec. Methods Individuals covered by the public drug insurance plan between April 2014 and March 2017 were included in our cohort to describe rates of antimicrobial dispensing per 1,000 person-years, per age group (0-17 years old, 18-64 years old and 65 years old or over) and category of chronic disease (respiratory, cardiovascular, diabetes, mental disorder, none of these). For 2014-2017, ratios of extended-to-narrow spectrum antimicrobials were computed and multivariate Poisson regression was used to measure the impact of categories of chronic diseases on rates of total antimicrobial dispensing (in prescriptions and defined daily doses). Results A total of 1 259 833 children-years, 5 281 026 person-years between 18 and 64 years and 3 841 359 person-years 65 years or older were included in the study. Ratios of extended-to-narrow spectrum antimicrobials varied from 3.1 (adults 18-64 years old with no chronic disease) to 14.6 (children with no chronic disease); ratios for individuals with chronic diseases were lower in children but higher in adults. Adults with chronic respiratory diseases were twice more exposed to antimicrobials (increase of 109%) than those with none of the studied diseases (62% increase in children). In adults, antimicrobial use was also 48% higher in presence of a mental disorder (22% in children), 40% higher with diabetes (102% in children) and 31% higher with a cardiovascular disease (no data in children). These differences were all statistically significant (α = 0,05). Conclusion In Québec, antimicrobial dispensation was more frequent for individuals with at least one chronic disease. This raises the question of how much antimicrobial use can be reduced or improved to limit the selection of resistant bacteria. Disclosures All Authors: No reported disclosures

695. Antipseudomonal Versus Narrow-spectrum Agents for the Treatment of Community-onset Intra-abdominal Infections

Background Antipseudomonal antibiotic regiments are often used to treat community-acquired intra-abdominal infections (CA-IAI) despite common causative pathogens being susceptible to more narrow-spectrum agents. The purpose of this study was to compare post-infection complications in adult patients treated for CA-IAI with antipseudomonal or narrow-spectrum regimens Methods This retrospective cohort study included patients ≥18 years admitted for CA-IAI treated with antibiotics between January 1, 2013, and December 31, 2019. Patients who had bacteremia or peritonitis were excluded. The primary objective of this study was to compare post-infection complications within 90 days between patients treated empirically with antipseudomonal versus narrow-spectrum regimens. Post-infection complication was defined as post-operative infection, recurrence of diverticulitis, or mortality. Secondary objectives were to compare infection and treatment characteristics along with patient outcomes. Sub-group analyses were planned to compare outcomes of patients with low-risk and high-risk CA-IAI and patients who required surgical intervention versus who were medically managed Results A total of 350 patients were included: Antipseudomonal, n=204; Narrow-spectrum, n=146. There were no differences in 90-day post-infection complications between groups (Antipseudomonal 15.1% vs Narrow-spectrum 11.3%, p=0.296). Additionally, no differences were observed in hospital LOS, 90-day readmission, C. difficile, or mortality. Patients treated with Antipseudomonal regimens received longer durations of therapy (median 11 days [IQR 8-14] vs 9 days [IQR 5-12], p&lt; 0.001). No differences were observed in 90-day post-infection complications for patient with low-risk (Antipseudomonal 15% vs Narrow-spectrum 9.6%, p=0.154) or high-risk CA-IAI (Antipseudomonal 15.8% vs Narrow-spectrum 22.2%, p=0.588), or those who were surgically (Antipseudomonal 8.5% vs Narrow-spectrum 9.2%, p=0.877) or medically managed (Antipseudomonal 17.5% vs Narrow-spectrum 13.1%, p=0.463). Conclusion Post-infection complication rates were similar among patients treated with antipseudomonal and narrow-spectrum antibiotics. Antipseudomonal therapy is likely unnecessary for most patients with CA-IAI Disclosures Lisa E. Dumkow, PharmD, BCIDP, Nothing to disclose